We are developing a novel, actively non-thrombogenic surface for the prevention of post-operative platelet dysfunction and consumption induced by cardiopulmonary bypass surgery. This proprietary material will be applied to the luminal surface of bypass circuitry as a micron- thick web composed of polyethyleneimine (PEI) nanofibers. The pharmacologic activity of the material results from the covalent linkage of PEI to a nitric oxide (NO) releasing diazeniumdiolate (PEI-NO). NO released from PEI-NO may depress the function of platelets transiting the bypass circuit via its activation of guanylyl cyclase. This should result in a localized and labile anti-platelet effect at the blood-graft interface. To confirm this hypothesis, we propose to demonstrate that PEI-NO reduces platelet activation in vivo. Specific Aim #1: Construct a PEI-NO sustained-release synthetic vascular circuit and characterize the specific activity and release profile of NO. We will first prepare sufficient quantities of PEI-NO nanofibers for micron-thick application to polyurethane tubing. Utilizing chemiluminescent analysis, we will calculate the yield and in vitro half-life of NO release under a variety of chemical and physical conditions. We will then compare the inhibition of platelet activation by PEI and PEI-NO coated circuits. Specific Aim #2: Demonstrate that PEI-NO surfaces reduce platelet adhesion and activation in an extracorporeal venovenous circuit. To determine the effect of PEI-NO NO-releasing nanofibers on platelet function in vivo, control and PEI-NO coated circuits will be exposed to extracorporeal circulation in a well-established lapine model. These animals are not anti-coagulated with heparin or given other agents known to affect platelet function. The accumulation of blood platelets is quantified by scintillation counting of platelets labeled with indium-111. Platelet deposition is also measured by electron microscopic analysis after removal and fixation of the graft. Platelet function will be assessed by aggregometry. We expect the above scope of work to validate the in vivo efficacy of PEI-NO as a novel non-thrombogenic surface material. On this basis, we plan in Phase II to optimize the chemistry and material processes to ensure a stable NO release profile suitable for clinical testing in cardiopulmonary bypass surgery. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective non-thrombogenic vascular catheter for use in cardiac bypass surgery is estimated at $50 million per annum, given an annual operative incidence of 500,000. Global markets are estimated $200 million. Funding of SBIR Phases I and II will allow for market entry in 3.5 years.